Severe, therapy-resistant asthma is a challenging disorder affecting ~10-15% of all asthmatics that is associated with persistent airway inflammation and progressive lung function deficits despite treatment with high doses of inhaled corticosteroids (ICS). Although the mechanisms underlying severe asthma are poorly understood, racial disparities are evident among affected patients and suggest a potential role for genetics in the modulation of the disorder. In the U.S., African Americans are nearly twice as likely (compared to whites) to have current severe asthma independent of socioeconomic status, resulting in a two-fold increase in hospitalizations and a four-fold increase in asthma death. Furthermore, African Americans are twice as likely to have persistent airflow limitation and progressive loss of lung function despite equivalent treatment. However, African Americans have been poorly represented in asthma studies and thus there is an urgent need for research targeting African Americans to unravel the mechanisms and genetic underpinnings of severe asthma in this high-risk population. Although genetic studies have identified single nucleotide polymorphisms (SNPs) associated with cross-sectional lung function measures in asthma patients, these studies were predominantly conducted in general populations of European whites and thus are of questionable relevance to African Americans. Furthermore, the clinical "utility" or "meaningfulness" of these SNPs in predicting other relevant asthma outcomes in this population remains unclear. Therefore, through a prospective, genotype- stratified cohort study, this application will determine whether SNPs in a panel of lung function genes predict asthma severity in African American children and adults with persistent asthma treated with ICS.
The specific aims are to: 1) stratify and phenotype African American children and adults with persistent asthma by genotype 2) determine whether genotype predicts longitudinal asthma severity in African American children and adults with persistent asthma, and 3) refine the gene model for asthma severity in African American children and adults with ancestral genetic markers. Emory and Wake Forest have a long history of collaboration and together have led the initiative for phenotypic and genomic analyses of severe asthma. The findings generated here are expected to generate novel information on the contribution of genomic variants to severe asthma in African Americans. Given the increased morbidity associated with asthma in African Americans, these findings will lay important groundwork to advance personalized genomics approaches for this challenging and understudied population. This study is also in keeping with the mission of the NINR to improve quality of life by managing the symptoms of chronic illnesses (severe asthma) and to enhance research innovation through application of interdisciplinary approaches to improve the health of asthma patients.

Public Health Relevance

The burden of asthma is significantly greater in African Americans and is highlighted by increased asthma- related hospitalizations and deaths despite equivalent treatment. To understand whether genetic differences underlie racial disparities associated with asthma, we will conduct a prospective, genotype-stratified cohort study to determine whether single nucleotide polymorphisms (SNPs) in a panel of genes predicts asthma severity (lung function decline and exacerbations) in African American children and adults with persistent asthma treated with ICS. These findings will generate novel information on the contribution of genomic variants to severe asthma in African Americans and will lay important groundwork to advance personalized medicine for this challenging and understudied population.